The objective of this population-based study is to develop new methods appropriate for analyzing familial aggregation of congenital malformations. In general, familial aggregation is well documented for many common malformations, however, analysis of familial recurrence is complicated by etiologic heterogeneity within individual phenotypic malformations and by the possibility that different phenotypic malformations may share common pathogenetic mechanisms. Therefore, we proposed a sequential approach where: 1) Cases with multiple malformations will be analysed using the log-linear model to identify malformations which are closely associated (other than syndromic malformations or those representing a known embryonic sequence). Such associated malformations will be critically evaluated using both clinical and epidemiologic data to maximize the homogeneity of these newly defined phenotypic groups. 2) Patterns of familial recurrence for groups of malformations identified in this manner will be analyzed using a modification of the logistic regression model which takes into account the natural dependence among relatives while simultaneously considering the effects of observable risk factors. Malformations which show a strong correlation in risk among sibs in this analysis are prime candidates for further genetic analysis. 3) Genetic analysis of such malformations in families will be carried out to test specific models of inheritance. Data for this project will be drawn from the Metropolitan Atlanta Congenital Defects Program which is a registry established in 1968 for malformations diagnosed during the first year of life. Parental interviews obtained as part of the Vietnam Veterans Birth Defects Study will provide family history data for 3739 case families to be used here. Ascertainment of malformations among sibs will be from interview data as well as through independent ascertainment in the registry for births after 1968. By systematically analyzing various congenital malformations to identify more homogeneous phenotypic groups, before conducting studies of familial aggregation and formal genetic analysis, we will improve our understanding of the etiologic mechanisms underlying major congenital malformations